I+D en área médica y farmacia clínica
Inmunoterapia CART: diseñar las células inmunitarias para tratar el propio cáncer
inmunoterapia cart
IM Médico
30 de mayo de 2016 17:56
Durante muchos años, la piedra angular del tratamiento del cáncer ha sido la cirugía, la quimioterapia o la radioterapia. En la última década se han desarrollado tratamientos dirigidos como imatinib (Gleevec®) y trastuzumab (Herceptin®), fármacos dirigidos contra las células cancerosas que se establecen en cambios moleculares específicos observados previamente en estas células.
Hoy en día la estrella es la inmunoterapia, un tratamiento que aprovecha el potencial del sistema inmunitario del paciente para combatir su propia enfermedad, lo cual se conoce entre los investigadores como el quinto pilar del tratamiento contra el cáncer. Uno de los enfoques de la inmunoterapia consiste en modificar las células inmunitarias del mismo paciente para que reconozca y ataque sus propios tumores. A pesar de que este enfoque, conocido como la transferencia adoptiva de linfocitos T (ACT, por sus siglas en inglés), se ha restringido solamente a pequeños ensayos clínicos, muchos tratamientos que utilizan células inmunitarias diseñadas han mostrado respuestas significativas en pacientes con cáncer en fase avanzada. Por ejemplo, varios pacientes con leucemia linfoblástica aguda en fase avanzada para los cuales no quedaba ninguna otra opción de tratamiento han visto desaparecer su cáncer totalmente tras participar en ensayos clínicos de fase inicial que utilizaban esta terapia.
La transferencia adoptiva de linfocitos T consiste en “administrar a los pacientes un fármaco vivo”, así lo afirma el doctor Renier J. Brentjens, del Memorial Sloan Kettering Cancer Center (MSKCC) de Nueva York. Este especialista lo define de esta manera ya que los linfocitos T, la parte fundamental de esta terapia, son un tipo de células inmunitarias recogidas de la misma sangre del paciente. Estas células se modifican genéticamente para que reproduzcan receptores especiales en su superficie llamados CAR (receptores de antígenos quiméricos).
Los CAR son proteínas que permiten que los linfocitos T reconozcan una proteína específica (antígeno) en las células tumorales. Tras cultivar los linfocitos T- CAR en el laboratorio y multiplicarlos, se introducen en el paciente donde, si todo va según lo planeado, se multiplican y, bajo la dirección de su receptor diseñado, reconocen y destruyen las células cancerosas que presentan el antígeno en sus superficies.
Este proceso es muy similar a una técnica ACT diseñada por Steven Rosenberg y sus compañeros del Instituto Nacional del Cáncer (NCI) estadounidense para tratar a los pacientes con melanoma en fase avanzada. “Los linfocitos T CAR son de lejos mucho más potentes que cualquier otra terapia basada en la inmunología”, afirma Crystal Mackall del NCI. Aun así, los investigadores advierten que todavía faltan muchos aspectos por estudiar y desarrollar de la terapia con linfocitos T CAR. No obstante, los resultados iniciales recogidos de ensayos clínicos generan un optimismo considerable. (…)
martes, 31 de mayo de 2016
sábado, 21 de mayo de 2016
Antiperspirants/Deodorants and Breast Cancer
Antiperspirants/Deodorants and Breast Cancer
Can antiperspirants or deodorants cause breast cancer?
What do scientists know about the ingredients in antiperspirants and deodorants?
What have scientists learned about the relationship between antiperspirants or deodorants and breast cancer?
Where can someone get more information on breast cancer risk?
Can antiperspirants or deodorants cause breast cancer?
Articles in the press and on the Internet have warned that underarm antiperspirants (a preparation that reduces underarm sweat) or deodorants (a preparation that destroys or masks unpleasant odors) cause breast cancer (1). The reports have suggested that these products contain harmful substances, which can be absorbed through the skin or enter the body through nicks caused by shaving. Some scientists have also proposed that certain ingredients in underarm antiperspirants or deodorants may be related to breast cancer because they are applied frequently to an area next to the breast (2, 3).
However, researchers at the National Cancer Institute (NCI), a part of the National Institutes of Health, are not aware of any conclusive evidence linking the use of underarm antiperspirants or deodorants and the subsequent development of breast cancer. The U.S. Food and Drug Administration (FDA), which regulates food, cosmetics, medicines, and medical devices, also does not have any evidence or research data that ingredients in underarm antiperspirants or deodorants cause cancer.
What do scientists know about the ingredients in antiperspirants and deodorants?
Aluminum-based compounds are used as the active ingredient in antiperspirants. These compounds form a temporary plug within the sweat duct that stops the flow of sweat to the skin's surface. Some research suggests that aluminum-based compounds, which are applied frequently and left on the skin near the breast, may be absorbed by the skin and cause estrogen-like (hormonal) effects (3). Because estrogen has the ability to promote the growth of breast cancer cells, some scientists have suggested that the aluminum-based compounds in antiperspirants may contribute to the development of breast cancer (3).
Some research has focused on parabens, which are preservatives used in some deodorants and antiperspirants that have been shown to mimic the activity of estrogen in the body’s cells (4). Although parabens are used in many cosmetic, food, and pharmaceutical products, according to the FDA, most major brands of deodorants and antiperspirants in the United States do not currently contain parabens. Consumers can look at the ingredient label to determine if a deodorant or antiperspirant contains parabens. Parabens are usually easy to identify by name, such as methylparaben, propylparaben, butylparaben, or benzylparaben. The National Library of Medicine’s Household Products Database also has information about the ingredients used in most major brands of deodorants and antiperspirants.
The belief that parabens build up in breast tissue was supported by a 2004 study, which found parabens in 18 of 20 samples of tissue from human breast tumors (5). However, this study did not prove that parabens cause breast tumors (4). The authors of this study did not analyze healthy breast tissue or tissues from other areas of the body and did not demonstrate that parabens are found only in cancerous breast tissue (5). Furthermore, this research did not identify the source of the parabens and cannot establish that the buildup of parabens is due to the use of deodorants or antiperspirants.
More research is needed to specifically examine whether the use of deodorants or antiperspirants can cause the buildup of parabens and aluminum-based compounds in breast tissue. Additional research is also necessary to determine whether these chemicals can either alter the DNA in some cells or cause other breast cell changes that may lead to the development of breast cancer.
What have scientists learned about the relationship between antiperspirants or deodorants and breast cancer?
In 2002, the results of a study looking for a relationship between breast cancer and underarm antiperspirants/deodorants were reported (6). This study did not show any increased risk for breast cancer in women who reported using an underarm antiperspirant or deodorant. The results also showed no increased breast cancer risk for women who reported using a blade (nonelectric) razor and an underarm antiperspirant or deodorant, or for women who reported using an underarm antiperspirant or deodorant within 1 hour of shaving with a blade razor. These conclusions were based on interviews with 813 women with breast cancer and 793 women with no history of breast cancer.
Findings from a different study examining the frequency of underarm shaving and antiperspirant/deodorant use among 437 breast cancer survivors were released in 2003 (7). This study found that the age of breast cancer diagnosis was significantly earlier in women who used these products and shaved their underarms more frequently. Furthermore, women who began both of these underarm hygiene habits before 16 years of age were diagnosed with breast cancer at an earlier age than those who began these habits later. While these results suggest that underarm shaving with the use of antiperspirants/deodorants may be related to breast cancer, it does not demonstrate a conclusive link between these underarm hygiene habits and breast cancer.
In 2006, researchers examined antiperspirant use and other factors among 54 women with breast cancer and 50 women without breast cancer. The study found no association between antiperspirant use and the risk of breast cancer; however, family history and the use of oral contraceptives were associated with an increased risk of breast cancer (8).
Because studies of antiperspirants and deodorants and breast cancer have provided conflicting results, additional research is needed to investigate this relationship and other factors that may be involved.
Where can someone get more information on breast cancer risk?
People who are concerned about their breast cancer risk are encouraged to talk with their doctor. More information about breast cancer risk can be found in the PDQ® Breast Cancer Prevention Summary for Patients.
U.S. residents may wish to contact the NCI's Cancer Information Service (CIS) with any remaining questions or concerns about breast cancer. The CIS can be reached at 1–800–4–CANCER or by e-mail.
Selected References
Jones J. Can rumors cause cancer?Exit Disclaimer Journal of the National Cancer Institute 2000; 92(18):1469–1471.
Darbre PD. Underarm cosmetics and breast cancer. Journal of Applied Toxicology 2003; 23(2):89–95. [PubMed Abstract]
Darbre PD. Aluminium, antiperspirants and breast cancer. Journal of Inorganic Biochemistry 2005; 99(9):1912–1919. [PubMed Abstract]
Harvey PW, Everett DJ. Significance of the detection of esters of p-hydroxybenzoic acid (parabens) in human breast tumours. Journal of Applied Toxicology 2004; 24(1):1–4. [PubMed Abstract]
Darbre PD, Aljarrah A, Miller WR, et al. Concentrations of parabens in human breast tumours. Journal of Applied Toxicology 2004; 24(1):5–13. [PubMed Abstract]
Mirick DK, Davis S, Thomas DB. Antiperspirant use and the risk of breast cancer. Journal of the National Cancer Institute 2002; 94(20):1578–1580. [PubMed Abstract]
McGrath KG. An earlier age of breast cancer diagnosis related to more frequent use of antiperspirants/deodorants and underarm shaving. European Journal of Cancer 2003; 12(6):479–485. [PubMed Abstract]
Fakri S, Al-Azzawi A, Al-Tawil N. Antiperspirant use as a risk factor for breast cancer in Iraq. Eastern Mediterranean Health Journal 2006; 12(3–4):478–482. [PubMed Abstract]
Related Resources
What You Need To Know About™ Breast Cancer
Reviewed: January 4, 2008
Can antiperspirants or deodorants cause breast cancer?
What do scientists know about the ingredients in antiperspirants and deodorants?
What have scientists learned about the relationship between antiperspirants or deodorants and breast cancer?
Where can someone get more information on breast cancer risk?
Can antiperspirants or deodorants cause breast cancer?
Articles in the press and on the Internet have warned that underarm antiperspirants (a preparation that reduces underarm sweat) or deodorants (a preparation that destroys or masks unpleasant odors) cause breast cancer (1). The reports have suggested that these products contain harmful substances, which can be absorbed through the skin or enter the body through nicks caused by shaving. Some scientists have also proposed that certain ingredients in underarm antiperspirants or deodorants may be related to breast cancer because they are applied frequently to an area next to the breast (2, 3).
However, researchers at the National Cancer Institute (NCI), a part of the National Institutes of Health, are not aware of any conclusive evidence linking the use of underarm antiperspirants or deodorants and the subsequent development of breast cancer. The U.S. Food and Drug Administration (FDA), which regulates food, cosmetics, medicines, and medical devices, also does not have any evidence or research data that ingredients in underarm antiperspirants or deodorants cause cancer.
What do scientists know about the ingredients in antiperspirants and deodorants?
Aluminum-based compounds are used as the active ingredient in antiperspirants. These compounds form a temporary plug within the sweat duct that stops the flow of sweat to the skin's surface. Some research suggests that aluminum-based compounds, which are applied frequently and left on the skin near the breast, may be absorbed by the skin and cause estrogen-like (hormonal) effects (3). Because estrogen has the ability to promote the growth of breast cancer cells, some scientists have suggested that the aluminum-based compounds in antiperspirants may contribute to the development of breast cancer (3).
Some research has focused on parabens, which are preservatives used in some deodorants and antiperspirants that have been shown to mimic the activity of estrogen in the body’s cells (4). Although parabens are used in many cosmetic, food, and pharmaceutical products, according to the FDA, most major brands of deodorants and antiperspirants in the United States do not currently contain parabens. Consumers can look at the ingredient label to determine if a deodorant or antiperspirant contains parabens. Parabens are usually easy to identify by name, such as methylparaben, propylparaben, butylparaben, or benzylparaben. The National Library of Medicine’s Household Products Database also has information about the ingredients used in most major brands of deodorants and antiperspirants.
The belief that parabens build up in breast tissue was supported by a 2004 study, which found parabens in 18 of 20 samples of tissue from human breast tumors (5). However, this study did not prove that parabens cause breast tumors (4). The authors of this study did not analyze healthy breast tissue or tissues from other areas of the body and did not demonstrate that parabens are found only in cancerous breast tissue (5). Furthermore, this research did not identify the source of the parabens and cannot establish that the buildup of parabens is due to the use of deodorants or antiperspirants.
More research is needed to specifically examine whether the use of deodorants or antiperspirants can cause the buildup of parabens and aluminum-based compounds in breast tissue. Additional research is also necessary to determine whether these chemicals can either alter the DNA in some cells or cause other breast cell changes that may lead to the development of breast cancer.
What have scientists learned about the relationship between antiperspirants or deodorants and breast cancer?
In 2002, the results of a study looking for a relationship between breast cancer and underarm antiperspirants/deodorants were reported (6). This study did not show any increased risk for breast cancer in women who reported using an underarm antiperspirant or deodorant. The results also showed no increased breast cancer risk for women who reported using a blade (nonelectric) razor and an underarm antiperspirant or deodorant, or for women who reported using an underarm antiperspirant or deodorant within 1 hour of shaving with a blade razor. These conclusions were based on interviews with 813 women with breast cancer and 793 women with no history of breast cancer.
Findings from a different study examining the frequency of underarm shaving and antiperspirant/deodorant use among 437 breast cancer survivors were released in 2003 (7). This study found that the age of breast cancer diagnosis was significantly earlier in women who used these products and shaved their underarms more frequently. Furthermore, women who began both of these underarm hygiene habits before 16 years of age were diagnosed with breast cancer at an earlier age than those who began these habits later. While these results suggest that underarm shaving with the use of antiperspirants/deodorants may be related to breast cancer, it does not demonstrate a conclusive link between these underarm hygiene habits and breast cancer.
In 2006, researchers examined antiperspirant use and other factors among 54 women with breast cancer and 50 women without breast cancer. The study found no association between antiperspirant use and the risk of breast cancer; however, family history and the use of oral contraceptives were associated with an increased risk of breast cancer (8).
Because studies of antiperspirants and deodorants and breast cancer have provided conflicting results, additional research is needed to investigate this relationship and other factors that may be involved.
Where can someone get more information on breast cancer risk?
People who are concerned about their breast cancer risk are encouraged to talk with their doctor. More information about breast cancer risk can be found in the PDQ® Breast Cancer Prevention Summary for Patients.
U.S. residents may wish to contact the NCI's Cancer Information Service (CIS) with any remaining questions or concerns about breast cancer. The CIS can be reached at 1–800–4–CANCER or by e-mail.
Selected References
Jones J. Can rumors cause cancer?Exit Disclaimer Journal of the National Cancer Institute 2000; 92(18):1469–1471.
Darbre PD. Underarm cosmetics and breast cancer. Journal of Applied Toxicology 2003; 23(2):89–95. [PubMed Abstract]
Darbre PD. Aluminium, antiperspirants and breast cancer. Journal of Inorganic Biochemistry 2005; 99(9):1912–1919. [PubMed Abstract]
Harvey PW, Everett DJ. Significance of the detection of esters of p-hydroxybenzoic acid (parabens) in human breast tumours. Journal of Applied Toxicology 2004; 24(1):1–4. [PubMed Abstract]
Darbre PD, Aljarrah A, Miller WR, et al. Concentrations of parabens in human breast tumours. Journal of Applied Toxicology 2004; 24(1):5–13. [PubMed Abstract]
Mirick DK, Davis S, Thomas DB. Antiperspirant use and the risk of breast cancer. Journal of the National Cancer Institute 2002; 94(20):1578–1580. [PubMed Abstract]
McGrath KG. An earlier age of breast cancer diagnosis related to more frequent use of antiperspirants/deodorants and underarm shaving. European Journal of Cancer 2003; 12(6):479–485. [PubMed Abstract]
Fakri S, Al-Azzawi A, Al-Tawil N. Antiperspirant use as a risk factor for breast cancer in Iraq. Eastern Mediterranean Health Journal 2006; 12(3–4):478–482. [PubMed Abstract]
Related Resources
What You Need To Know About™ Breast Cancer
Reviewed: January 4, 2008
miércoles, 18 de mayo de 2016
Increasing the Interval Between Neoadjuvant Chemoradiotherapy and Surgery in Rectal Cancer
Annals of Surgery
Increasing the Interval Between Neoadjuvant Chemoradiotherapy and Surgery in Rectal Cancer
A Meta-analysis of Published Studies
Fausto Petrelli, MD; Giovanni Sgroi, MD; Enrico Sarti, MD; Sandro Barni, MD
Disclosures
Annals of Surgery. 2016;263(3):458-464.
Abstract and Introduction
Abstract
Objective: The aim of this meta-analysis was to demonstrate whether a longer interval between the end of neoadjuvant chemoradiotherapy (CRT) and surgery is associated with a better rate of pathological complete response (pCR) in rectal cancer.
Background: The standard of care in locally advanced rectal cancer is preoperative, long course (5-fluorouracil-based) CRT. After this neoadjuvant CRT, surgical exploration is undertaken 6 to 8 weeks later.
Methods: PubMed, EMBASE, the ISI Web of Science, and The Cochrane Library (CENTRAL) were searched systematically for prospective or retrospective studies reporting oncological results for intervals longer or shorter than 6 to 8 weeks between the end of CRT and surgery, in rectal cancer. The primary endpoint, reported as relative risk (RR), was the rate of pCR. Secondary endpoints were overall survival (OS), disease-free survival (DFS), R0 resection rates, sphincter preservations, and wound/anastomotic complications. A meta-analysis was performed, using the fixed- or random-effects model, with Review Manager 5.1.
Results: Thirteen trials, including 3584 patients, were identified, and overall, an interval longer than 6 to 8 weeks from the end of neoadjuvant CRT and surgery significantly improved the pCR (RR = 1.42, 95% confidence interval: 1.19–1.68; P < 0.0001). Pathological complete responses increased from 13.7% to 19.5% in the longer interval group, and the OS, DFS, R0 resection rates, sphincter preservation, and complication rates were similar in the 2 groups. Conclusions: A longer waiting interval (more than the classical 6–8 weeks) from the end of preoperative CRT increases the rate of pCR by 6% in rectal cancer, with similar outcomes and complication rates. These results should be validated prospectively in a randomized trial.
viernes, 13 de mayo de 2016
Nivolumab: New indications concern the treatment of renal cell carcinoma and non-squamous NSCLC
EMA Recommends Extending the Use of Nivolumab
New indications concern the treatment of renal cell carcinoma and non-squamous NSCLC
Date: 26 Feb 2016
Topic: Genitourinary cancers / Lung and other thoracic tumours / Cancer Immunology and Immunotherapy
On 25 February 2016, the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) adopted two positive opinions recommending changes to the terms of the marketing authorisation for the medicinal product nivolumab (Opdivo). The CHMP has recommended extending the use nivolumab to include the treatment of adult patients with advanced renal cell carcinoma who have received prior therapy. Another extension of indication recommends use of nivolumab as a monotherapy in locally-advanced or metastatic non-squamous non-small cell lung cancer (NSCLC).
Nivolumab was first authorised in the European Union (EU) in June 2015 for the treatment of advanced melanoma and already had its use extended in October 2015 to treatment of the advanced stages of squamous NSCLC.
The active substance in Opdivo – nivolumab – is a monoclonal antibody. Nivolumab attaches to and blocks a receptor called programmed death-1 (PD-1). By blocking the usual receptor interactions, nivolumab leads to activation of the immune system against cancer cells.
The recommendation from the EMA’s CHMP is based on the results of a randomised phase III study evaluating nivolumab versus everolimus. In total, 821 patients with locally advanced or metastatic renal cell carcinoma whose disease progressed during or after treatment with anti-angiogenic therapy were included in the study.
The median survival time after starting treatment in patients taking nivolumab was 25 months compared to just under 20 months in patients treated with everolimus.
In addition, about 22% of patients taking nivolumab saw a complete or partial shrinkage of their tumours compared to 4% of those taking everolimus; on average the effect lasted around 12 months for both groups.
The most common side effects of nivolumab reported during the clinical trial were similar to those observed in the already approved indications of nivolumab. These include fatigue, nausea, rash, diarrhoea and decreased appetite.
Another extension of indication was also approved by the CHMP this month, recommending use of nivolumab as a monotherapy in locally advanced or metastatic non-squamous NSCLC.
Detailed recommendations for the use of this product will be described in the updated summary of product characteristics, which will be published in the revised European public assessment report, and will be available in all official EU languages after a decision on this change to the marketing authorisation has been granted by the European Commission.
The opinions adopted by the CHMP at its February 2016 meeting are an intermediary step on nivolumab’s path to patient access. The CHMP opinions will now be sent to the European Commission for the adoption of a decision on EU-wide marketing authorisations. Once the extensions of indications have been granted, a decision about price and reimbursement will take place at the level of each Member State considering the potential role/use of this medicine in the context of the national health system of that country.
The marketing authorisation holder for this medicinal product is Bristol-Myers Squibb Pharma EEIG.
New indications concern the treatment of renal cell carcinoma and non-squamous NSCLC
Date: 26 Feb 2016
Topic: Genitourinary cancers / Lung and other thoracic tumours / Cancer Immunology and Immunotherapy
On 25 February 2016, the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) adopted two positive opinions recommending changes to the terms of the marketing authorisation for the medicinal product nivolumab (Opdivo). The CHMP has recommended extending the use nivolumab to include the treatment of adult patients with advanced renal cell carcinoma who have received prior therapy. Another extension of indication recommends use of nivolumab as a monotherapy in locally-advanced or metastatic non-squamous non-small cell lung cancer (NSCLC).
Nivolumab was first authorised in the European Union (EU) in June 2015 for the treatment of advanced melanoma and already had its use extended in October 2015 to treatment of the advanced stages of squamous NSCLC.
The active substance in Opdivo – nivolumab – is a monoclonal antibody. Nivolumab attaches to and blocks a receptor called programmed death-1 (PD-1). By blocking the usual receptor interactions, nivolumab leads to activation of the immune system against cancer cells.
The recommendation from the EMA’s CHMP is based on the results of a randomised phase III study evaluating nivolumab versus everolimus. In total, 821 patients with locally advanced or metastatic renal cell carcinoma whose disease progressed during or after treatment with anti-angiogenic therapy were included in the study.
The median survival time after starting treatment in patients taking nivolumab was 25 months compared to just under 20 months in patients treated with everolimus.
In addition, about 22% of patients taking nivolumab saw a complete or partial shrinkage of their tumours compared to 4% of those taking everolimus; on average the effect lasted around 12 months for both groups.
The most common side effects of nivolumab reported during the clinical trial were similar to those observed in the already approved indications of nivolumab. These include fatigue, nausea, rash, diarrhoea and decreased appetite.
Another extension of indication was also approved by the CHMP this month, recommending use of nivolumab as a monotherapy in locally advanced or metastatic non-squamous NSCLC.
Detailed recommendations for the use of this product will be described in the updated summary of product characteristics, which will be published in the revised European public assessment report, and will be available in all official EU languages after a decision on this change to the marketing authorisation has been granted by the European Commission.
The opinions adopted by the CHMP at its February 2016 meeting are an intermediary step on nivolumab’s path to patient access. The CHMP opinions will now be sent to the European Commission for the adoption of a decision on EU-wide marketing authorisations. Once the extensions of indications have been granted, a decision about price and reimbursement will take place at the level of each Member State considering the potential role/use of this medicine in the context of the national health system of that country.
The marketing authorisation holder for this medicinal product is Bristol-Myers Squibb Pharma EEIG.
Immunotherapy With Live Bacterium Improves Response Rate in Malignant Pleural Mesothelioma
ELCC 2016 Press Release: Immunotherapy With Live Bacterium Improves Response Rate in Malignant Pleural Mesothelioma
Date: 14 Apr 2016
Topic: Lung and other thoracic tumours / Cancer Immunology and Immunotherapy
GENEVA, Switzerland – Immunotherapy with a live bacterium combined with chemotherapy demonstrated more than 90% disease control and 59% response rate in patients with malignant pleural mesothelioma (MPM), according to the results of a phase Ib trial presented today at the European Lung Cancer Conference (ELCC) 2016 in Geneva, Switzerland.1
“Malignant pleural mesothelioma is a cancer of the lining of the lung and is rare but difficult to treat,” said Prof Thierry Jahan, professor of medicine at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, US. “Standard of care treatment with pemetrexed and platinum compound chemotherapy gets a 30% response rate but a modest impact on survival. So there is a clear unmet need in targeting this specific population.”
Patients with MPM strongly express the mesothelin antigen in the tumour. CRS-207 is a live, attenuated Listeria monocytogenes bacterium that contains two gene deletions to diminish its pathogenicity and has also been engineered to express mesothelin.
“In our early studies, CRS-207 induced an anti-mesothelin response and cellular tumour specific immunity in patients with mesothelin expressing tumours,” said Jahan. “We also have data suggesting that this immunotherapy works synergistically with chemotherapy, so testing the effect of this immune targeting agent with chemotherapy was a natural step.”
The current study examined the impact of CRS-207 combined with standard chemotherapy in patients with advanced unresectable mesothelioma who were candidates for chemotherapy. It included 38 patients who received two CRS-207 infusions two weeks apart, up to six cycles of pemetrexed plus cisplatin three weeks apart, followed by two additional CRS-207 infusions three weeks apart. Eligible patients received maintenance CRS-207 every eight weeks. Patients were followed every eight weeks until disease progression.
After a median follow up of 9.4 months (range: 0.2–28.1 months), the investigators found that 59% of patients had partial response and 35% had stable disease, for an overall 94% disease control rate. Median progression free survival was 8.5 months. Jahan said: “Patients receiving the combination of CRS-207 and chemotherapy had a deep response, with more than 90% disease control.”
The primary side-effects associated with CRS-207 administration were temperature spike and rigors. These were related to the infusion and resolved within 24 hours. “The safety of the agent was remarkable,” said Jahan. “It really does appear to be safe, and was well-tolerated in combination with pemetrexed and platinum chemotherapy. There didn’t seem to be any cumulative toxicity.”
Immunohistochemistry analysis in three patients showed marked recruitment and expansion of tumour infiltrating leukocytes following the administration of the therapy. There was also an enhancement of infiltrating CD8+ cells, macrophages and natural killer cells.
Jahan said: “We saw good immune activation which confirmed the preclinical hypotheses for utilising this agent. It appears to activate both innate and adaptive immunity and then develops a synergistic efficacy with the chemotherapy.”
He concluded: “CRS-207 is an exciting agent for patients with mesothelioma. Our preliminary results are encouraging, suggesting superior clinical activity when added to standard chemotherapy. This supports assessing the impact of CRS-207 in a randomised trial, which is currently in the planning stages and should be underway within this calendar year.”
Commenting on the research, Prof Rolf Stahel, Professor of oncology at the University Hospital Zurich in Zurich, Switzerland, said: “The findings suggest that the addition of this type of immunotherapy improves the response rate, and provides a longer progression free survival, compared to what would be expected with chemotherapy alone. This supports the hypothesis of benefit of this vaccination which will be examined in a randomised trial to prove or disprove the survival benefit of vaccination added to chemotherapy.”
-END-
References
208O_PR: CRS-207 with chemotherapy (chemo) in malignant pleural mesothelioma (MPM): Results from a phase 1b trial. T. Jahan, US. Thursday 14th April 2016 – 17:45-18:00 Multidisciplinary management of thoracic malignancies Room A
Date: 14 Apr 2016
Topic: Lung and other thoracic tumours / Cancer Immunology and Immunotherapy
GENEVA, Switzerland – Immunotherapy with a live bacterium combined with chemotherapy demonstrated more than 90% disease control and 59% response rate in patients with malignant pleural mesothelioma (MPM), according to the results of a phase Ib trial presented today at the European Lung Cancer Conference (ELCC) 2016 in Geneva, Switzerland.1
“Malignant pleural mesothelioma is a cancer of the lining of the lung and is rare but difficult to treat,” said Prof Thierry Jahan, professor of medicine at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, US. “Standard of care treatment with pemetrexed and platinum compound chemotherapy gets a 30% response rate but a modest impact on survival. So there is a clear unmet need in targeting this specific population.”
Patients with MPM strongly express the mesothelin antigen in the tumour. CRS-207 is a live, attenuated Listeria monocytogenes bacterium that contains two gene deletions to diminish its pathogenicity and has also been engineered to express mesothelin.
“In our early studies, CRS-207 induced an anti-mesothelin response and cellular tumour specific immunity in patients with mesothelin expressing tumours,” said Jahan. “We also have data suggesting that this immunotherapy works synergistically with chemotherapy, so testing the effect of this immune targeting agent with chemotherapy was a natural step.”
The current study examined the impact of CRS-207 combined with standard chemotherapy in patients with advanced unresectable mesothelioma who were candidates for chemotherapy. It included 38 patients who received two CRS-207 infusions two weeks apart, up to six cycles of pemetrexed plus cisplatin three weeks apart, followed by two additional CRS-207 infusions three weeks apart. Eligible patients received maintenance CRS-207 every eight weeks. Patients were followed every eight weeks until disease progression.
After a median follow up of 9.4 months (range: 0.2–28.1 months), the investigators found that 59% of patients had partial response and 35% had stable disease, for an overall 94% disease control rate. Median progression free survival was 8.5 months. Jahan said: “Patients receiving the combination of CRS-207 and chemotherapy had a deep response, with more than 90% disease control.”
The primary side-effects associated with CRS-207 administration were temperature spike and rigors. These were related to the infusion and resolved within 24 hours. “The safety of the agent was remarkable,” said Jahan. “It really does appear to be safe, and was well-tolerated in combination with pemetrexed and platinum chemotherapy. There didn’t seem to be any cumulative toxicity.”
Immunohistochemistry analysis in three patients showed marked recruitment and expansion of tumour infiltrating leukocytes following the administration of the therapy. There was also an enhancement of infiltrating CD8+ cells, macrophages and natural killer cells.
Jahan said: “We saw good immune activation which confirmed the preclinical hypotheses for utilising this agent. It appears to activate both innate and adaptive immunity and then develops a synergistic efficacy with the chemotherapy.”
He concluded: “CRS-207 is an exciting agent for patients with mesothelioma. Our preliminary results are encouraging, suggesting superior clinical activity when added to standard chemotherapy. This supports assessing the impact of CRS-207 in a randomised trial, which is currently in the planning stages and should be underway within this calendar year.”
Commenting on the research, Prof Rolf Stahel, Professor of oncology at the University Hospital Zurich in Zurich, Switzerland, said: “The findings suggest that the addition of this type of immunotherapy improves the response rate, and provides a longer progression free survival, compared to what would be expected with chemotherapy alone. This supports the hypothesis of benefit of this vaccination which will be examined in a randomised trial to prove or disprove the survival benefit of vaccination added to chemotherapy.”
-END-
References
208O_PR: CRS-207 with chemotherapy (chemo) in malignant pleural mesothelioma (MPM): Results from a phase 1b trial. T. Jahan, US. Thursday 14th April 2016 – 17:45-18:00 Multidisciplinary management of thoracic malignancies Room A
Acquired Resistance to Immunotherapy
Acquired Resistance to Immunotherapy
Future challenges in onco-immunology
Date: 18 Feb 2016
Topic: Cancer Immunology and Immunotherapy
Advances in immunotherapy have resulted in significant clinical responses in some patients with cancer. However, one of the biggest challenges in cancer therapeutics is the development of resistant disease and disease progression on or after therapy. Nature Reviews Cancer asked three scientists to give their views on the current evidence for whether acquired resistance to immunotherapy exists in patients and the future challenges posed by immunotherapy. Below we present some of the answers provided by scientists from the US National Cancer Institute, QIMR Berghofer Medical Research Institute in Brisbane, and Memorial Sloan Kettering Cancer Center.
Are there examples of acquired resistance to immunotherapy from clinical trials and model systems, and what are the characteristics of acquired resistance?
N.Restifo: “Before we discuss issues of resistance to immunotherapy, it should be duly noted that immunotherapy is a true paradigm shift in the treatment of patients with metastatic cancer. In terms of lives saved and person-years restored, immunotherapy promises to be more significant than any other form of treatment for patients whose tumours have already metastasized…
… immunotherapy can induce complete and long-lasting tumour regression. Thus, immune-selective pressure for resistant tumour cells must exist, but cause and effect relationships, especially in humans, cannot be drawn with any certainty. Nevertheless, we can theorize about what seems to be happening in our patients, and it is important to distinguish two major categories of acquired resistance of tumour masses to immunotherapy… selection of resistant clones and true acquired homeostatic resistance…”
Mark Smyth: “Several immunotherapies, in particular immune checkpoint-targeting antibodies and adoptive T cell therapies (ACTs), are beginning to transform the treatment of advanced cancers. The likelihood of response to these immunotherapies differs strongly across tumour types, and even in those cancer types that respond … non-responsiveness is observed, indicating the presence of intrinsic resistance or acquired immune resistance. In addition, in a subgroup of patients who do initially respond to immunotherapy, the cancer will later recur, thereby indicating a role of immunotherapy-induced acquired resistance. Intrinsic resistance often occurs in patients with global immunosuppression (for example, patients with HIV and some elderly patients), in tumours that express few molecular cues that can be recognized as foreign to the immune system (for example, non-viral tumours with a low mutational load) or in tumours that display intrinsic resistance to immune-mediated killing mechanisms.
There are many experimental and clinical examples of naturally acquired or immunotherapy-acquired resistance. Multiple inhibitory feedback mechanisms have a role in suppressing T cells in the tumour microenvironment (TME). These comprise the now clinically validated PD1–PDL1 axis and various potentially overlapping immune checkpoint molecules defined by preclinical studies… The general mechanisms of therapy-induced acquired resistance are likely to be very similar to those associated with naturally acquired resistance.”
Alexandra Snyder: “The frequency of acquired resistance to checkpoint blockade immunotherapies has not been systematically documented, although it is well known to clinicians who use such therapies…
The immune-related response criteria (irRC) have been developed to account for the growth patterns unique to immunotherapy-treated patients, specifically to allow for continued treatment on study beyond apparent progression, as some patients experience tumour growth followed by regression. In contrast to RECIST, using irRC, the appearance of new lesions does not automatically indicate progression. In addition, apparent progressive disease must be confirmed 4 weeks after the first immune-related progressive disease (irPD) assessment to qualify as true progression. irRC is often incorporated into immunotherapy trials, although this method does not specifically capture the acquired resistance group…
Clinically, patients who experience acquired resistance to PD1, PDL1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) antagonists can be conceived of in two broad categories: those patients who experience systemic disease control indefinitely with outgrowth of one to three discordant lesions, termed oligometastatic progression; and those patients who experience temporary systemic disease control followed by tumour growth at all or most sites. However, the true frequency and possible agent-specific nature of such phenomena have not yet been studied. Anecdotally, acquired resistance to anti-PD1 therapy … seems to occur more often in the second pattern, with fewer cases of isolated discordant lesions such as those that have been described upon treatment with ipilimumab. However, there are exceptions…
It is possible that earlier treatment of patients in the metastatic or adjuvant setting could mitigate the development of discordant or escape lesions; however, the exposure of patients (a subset of whom may be cured) to agents that carry a risk of side effects has limited such studies to date.”
Is there evidence of immunoediting as a mechanism of acquired immunotherapy resistance?
N. Restifo: “… there is substantial evidence for immunosurveillance in humans… The strongest arguments against immunoediting are the powerful, complete and durable responses we observe in the clinic. These responses seem to be the result of T cells recognizing mutated antigens…”
M. Smyth: “Cancer immunoediting is the process by which the immune system controls tumour outgrowth and shapes tumour immunogenicity, and it comprises three phases: elimination, equilibrium and escape.
…natural immunity to human tumours cannot easily be studied functionally in the absence of the genetic tools and controls afforded by animal studies. But advances in next-generation sequencing and epitope prediction now permit the definition of T cell responses against mutant antigens within individual patients, and should now allow the natural immunological history of a patient's tumour to be followed both before and after therapy.”
A. Snyder: “Preclinical data suggest a multitude of potential mechanisms for tumour evasion of checkpoint blockade immunotherapies; to date, immunoediting has not been confirmed in patients treated with checkpoint blockade, although studies of acquired resistance lesions are under way…
Four studies have now illustrated a correlation between elevated mutation burden and response to therapy with anti-CTLA4 or anti-PD1 agents, but these studies evaluate one tumour per patient. These studies also showed that neoantigen burden and mutation burden were correlated, and thus that neoantigen burden is associated with response. However, accurate neoantigen prediction in patients remains a challenge, and requires optimization using a more sophisticated bioinformatic and statistical approach accompanied by in vitro experimentation.”
What do you see as currently the biggest problems facing immunotherapy?
N. Restifo: “…I think there are three problems that deserve to be singled out. It is clear that most successful immunotherapies to date depend on T cells, but the characteristics of highly effective T cells remain largely unknown…The second problem concerns elucidation of the realm of structures that can serve as appropriate target antigens on tumour cells… third major problem facing researchers in the field of immunotherapy: understanding the nature of the target structures recognized by naturally occurring T cells.
As the field moves forward, it seems prudent to offer a more general point about the perils of the statistical analysis of very large data sets. Big data will invariably produce very precise answers, but as the data sets continue to grow the problem of potentially false findings exponentially expands as well. There is no question that high-throughput sequencing has opened vast new horizons. But statisticians since the time of Thomas Bayes have worried about the perils of understanding the world through data. In order to protect ourselves from the traps of big data, we must never forget to take the refuge afforded by cross-validation using independent data sets, especially when the number of parameters available becomes almost inconceivably large.”
M. Smyth: Immunotherapy faces many problems, including those that have been faced by conventional treatments in the past — for example, therapeutic resistance and affordability to all patients — as well as new challenges such as immune-associated adverse events. Rather than being a problem, the greatest challenge immunotherapy faces is rationalizing, while broadening, its utility… Anti-PD1 and anti-PDL1 monoclonal antibodies will likely represent the foundation of many future cancer treatments in type I tumours (defined as PDL1 positive with TILs driving adaptive immune resistance), and immediately the opportunities to combine these agents with surgery, immunogenic chemotherapy and targeted therapy and radiotherapy are obvious. This will account for a good proportion of patients with immunogenic and highly mutated tumours. While an alternative approach using ACT with chimeric antigen receptor (CAR)-engineered T cells brings together elements of treatment relevant to tumours with a TME that lacks T cells, its specificity will need to be paramount. By giving combination therapies to patients earlier, we would expect that up to 50% or more of some cancer types (such as melanoma and renal cell carcinoma) might be effectively controlled for long periods of time.
A large proportion of tumours with an 'immune-ignorant' phenotype (type II; PDL1 negative with no TILs) have a very poor prognosis regardless of any current treatment intervention, and they will require a completely new strategy. This group of patients represents the greatest challenge to immunotherapy and other cancer treatments. It is likely that these tumours will often have strong simple genetic drivers creating no or few neoantigens.”
A. Snyder: “Two of the biggest problems facing checkpoint blockade immunotherapy are scientific and societal. The success of dual therapy with the anti-CTLA4 agent ipilimumab and the anti-PD1 agent nivolumab in patients with metastatic melanoma suggests that combining such agents holds the promise of benefiting a higher proportion of patients with more durable disease control. However, the number of potential rational combinations is dizzying… Furthermore, there are preclinical data to suggest that such agents might also be successfully combined with other therapeutic modalities such as radiation, chemotherapy or CAR-engineered T cell ACT. In addition, the timing of such combinations is likely to be crucial to their efficacy… In the setting of such challenges, the publication of negative data — failed preclinical combinations and dosing schedules — could facilitate the more efficient translation of effective combinations to clinical trials. Finally, although immunotherapy is certainly an important component of cancer therapy, it may not be the universal panacea for all cancers, especially when considered as a single intervention.
The second, societal, issue is intimately tied to the first… The high cost of antibody therapies will weigh heavily on health-care systems that are already overstrained, in part by the cost of cancer care. If the durability of benefit seen with ipilimumab and nivolumab combination in melanoma was also seen in other malignancies, the drug cost might be seen as an 'up-front investment' in the health of patients who would otherwise be sustained on serial lines of chemotherapies that are themselves costly. Setting a higher bar for response could achieve the goal of only advancing towards the approval process those combinations for which the tremendous cost is offset by sustained efficacy in the majority of patients.”
The full article you can read in the ESMO Journals Access programme.
Reference
Restifo NP, Smyth MJ, and Snyder A. Acquired resistance to immunotherapy and future challenges. Nature Reviews Cancer 2016; 16: 121–126.
miércoles, 11 de mayo de 2016
Loneliness, Isolation May Increase CHD and Stroke Risk
Heartwire from Medscape
Loneliness, Isolation May Increase CHD and Stroke Risk
Deborah Brauser
April 22, 2016
YORK, UK — Although past research has shown a link between impaired social relationships and premature mortality, a new meta-analysis suggests there may also be a significant association with increased risk for coronary heart disease (CHD) and stroke[1].
The review of 23 papers and 181,006 total patients showed a 29% increased risk for incident CHD for those who had poor social connections, shown through loneliness and social-isolation measurements, compared with those with better connections. The lonely and isolated patients also had a 32% increased risk for stroke.
The investigators, led by Dr Nicole K Valtorta (University of York, UK), note that loneliness often contributes to impaired coping methods, isolation affects self-efficacy, and both have been associated with decreased physical activity and increased smoking.
They add that future studies are needed to assess whether targeting these social characteristics "can help to prevent two of the leading causes of death and disability in high-income countries." But for now, "health practitioners have an important role to play in acknowledging the importance of social relations to their patients."
The findings were published online April 18, 206 in Heart.
In an accompanying editorial[2], Drs Julianne Holt-Lunstad and Timothy B Smith (both from Brigham Young University, Provo, UT) point out that the results "are consistent with substantial research indicating broad health risks" from poor quality and quantity of social connectivity.
With the new findings adding to the literature, and because of predicted increases in impaired social relationships throughout North America and Europe, "medical science needs to squarely address the ramifications for physical health," write the editorialists.
"Include Social Factors in Medical Training"
After examination of 16 health databases, the investigators' final review included 23 studies, with 4628 total CHD events and 3002 stroke events, and follow-ups ranging from 3 to 21 years. Of the studies examined, 18 had social-isolation measurements only, three had loneliness measurements, and two had measurements of both. Also, 18 studies measured CHD and 10 measured stroke—with five reporting on both.
In addition, each study in the current analysis had 98 to 47,713 participants.
The pooled relative risk (RR) for incident CHD was 1.29 for the participants who reported having high loneliness or social-isolation scores vs those with low scores (95% CI 1.0–1.6). There were no significant differences between those who reported just loneliness and those who reported just social isolation.
The association found between poor social relationships and CHD was "comparable in size to other recognized psychosocial risk factors, such as anxiety and job strain," note the researchers.
In addition, the RR for stroke for patients with poor social characteristics was 1.32 (95% CI 1.0–1.7).
"The cumulative evidence points to the benefit of including social factors in medical training and continuing education for healthcare professionals," write the editorialists.
They add that just as cardiologists and other clinicians "have taken strong public stances" when it comes to other CVD-exacerbating factors, "further attention to social connections is needed in research and public-health surveillance, prevention, and intervention efforts."
The study was funded by the National Institute for Health Research, Research Trainees Coordinating Center. The study authors and editorialists have disclosed no relevant financial relationships.
Follow Deborah Brauser on Twitter: @heartwireDeb. For more from theheart.org, follow us on Twitter and Facebook.
Loneliness, Isolation May Increase CHD and Stroke Risk
Deborah Brauser
April 22, 2016
YORK, UK — Although past research has shown a link between impaired social relationships and premature mortality, a new meta-analysis suggests there may also be a significant association with increased risk for coronary heart disease (CHD) and stroke[1].
The review of 23 papers and 181,006 total patients showed a 29% increased risk for incident CHD for those who had poor social connections, shown through loneliness and social-isolation measurements, compared with those with better connections. The lonely and isolated patients also had a 32% increased risk for stroke.
The investigators, led by Dr Nicole K Valtorta (University of York, UK), note that loneliness often contributes to impaired coping methods, isolation affects self-efficacy, and both have been associated with decreased physical activity and increased smoking.
They add that future studies are needed to assess whether targeting these social characteristics "can help to prevent two of the leading causes of death and disability in high-income countries." But for now, "health practitioners have an important role to play in acknowledging the importance of social relations to their patients."
The findings were published online April 18, 206 in Heart.
In an accompanying editorial[2], Drs Julianne Holt-Lunstad and Timothy B Smith (both from Brigham Young University, Provo, UT) point out that the results "are consistent with substantial research indicating broad health risks" from poor quality and quantity of social connectivity.
With the new findings adding to the literature, and because of predicted increases in impaired social relationships throughout North America and Europe, "medical science needs to squarely address the ramifications for physical health," write the editorialists.
"Include Social Factors in Medical Training"
After examination of 16 health databases, the investigators' final review included 23 studies, with 4628 total CHD events and 3002 stroke events, and follow-ups ranging from 3 to 21 years. Of the studies examined, 18 had social-isolation measurements only, three had loneliness measurements, and two had measurements of both. Also, 18 studies measured CHD and 10 measured stroke—with five reporting on both.
In addition, each study in the current analysis had 98 to 47,713 participants.
The pooled relative risk (RR) for incident CHD was 1.29 for the participants who reported having high loneliness or social-isolation scores vs those with low scores (95% CI 1.0–1.6). There were no significant differences between those who reported just loneliness and those who reported just social isolation.
The association found between poor social relationships and CHD was "comparable in size to other recognized psychosocial risk factors, such as anxiety and job strain," note the researchers.
In addition, the RR for stroke for patients with poor social characteristics was 1.32 (95% CI 1.0–1.7).
"The cumulative evidence points to the benefit of including social factors in medical training and continuing education for healthcare professionals," write the editorialists.
They add that just as cardiologists and other clinicians "have taken strong public stances" when it comes to other CVD-exacerbating factors, "further attention to social connections is needed in research and public-health surveillance, prevention, and intervention efforts."
The study was funded by the National Institute for Health Research, Research Trainees Coordinating Center. The study authors and editorialists have disclosed no relevant financial relationships.
Follow Deborah Brauser on Twitter: @heartwireDeb. For more from theheart.org, follow us on Twitter and Facebook.
Social Media in Oncology: Does It Help Patients?
Medscape Oncology > Viewpoints
COMMENTARY
Social Media in Oncology: Does It Help Patients?
David Graham, MD
Disclosures | May 03, 2016
The growth of social media in medicine, particularly oncology, has been impressive. The uses to date have varied from live reporting of meeting presentations to community development and support in any number of diseases. The American Society of Clinical Oncology (ASCO) 2015 Annual Meeting had over 74,000 tweets in the month surrounding the actual meeting dates, leading to over 330 million impressions. An "impression" is a tweet that has been delivered to a feed. To relate it to the statistic above, tweets from the ASCO annual meeting were delivered to over 330 million feeds. The 2016 American College of Cardiology conference has had over 31,000 tweets leading to over 197 million impressions. This is just a small sampling of all the information that comes out of conferences.
Using social media for disease/treatment community development and support is also expanding. From dedicated Facebook pages to live Twitter chats, patients now interact with providers and advocates, often in real time. As I write this column, Symplur, a company that monitors and analyzes social media activity in medicine, reports 127 recurring Twitter chats in the upcoming week. Topics vary from rheumatoid arthritis, autism, and movement disorders to various malignancies, among many others.
Now that social media has a firm foothold in medicine, it becomes reasonable to ask whether it is having any impact on patient care or outcomes. This question has been raised in any number of supportive activities in medicine. There are certainly reports that online support groups benefit patients,[1] but the definition of benefit has tended to be somewhat nebulous at best. The first question to ask is, what is an appropriate thing to measure?
Now that social media has a firm foothold in medicine, it becomes reasonable to ask whether it is having any impact on patient care or outcomes.
In oncology, our usual measured outcome is survival, although quality of life is often co-reported. Quality of life, however, is rarely the primary outcome looked at in any intervention. There have been suggestions that support groups can improve survival in breast cancer, but at least one randomized trial failed to show any impact on survival in breast cancer patients.[2] Is survival the only outcome that we should measure? Can we accept improvements in quality of life as an actionable outcome? What if we show that patients who are involved in social media communities are more likely to be compliant with their care or be more open to clinical trial participation? Would that information be persuasive enough to have granting organizations, institutions, and payers be more open to providing support and recognition to the physicians and support staff involved in these activities?
Answering these questions will take a level of analysis and research that requires external support. To even get to the level of information and structure that granting organizations will be open to reviewing requires some firming up of ideas. There are physicians who are mulling these questions and starting down this path.[3] One such group in development is the Collaboration for Outcomes on Social Media in Oncology (COSMO). This group, of which I am a member, is looking at this with a blank slate, other than initially defining the best questions to ask. We have no hesitation—should the data point in this direction—saying that no positive impact can be determined by these efforts. We also have no problem saying that others may have thoughts on questions to be asked or approaches to take. In the spirit of crowdsourcing, we welcome any input. There are rumblings of an abstract to be presented at the next ASCO Annual Meeting suggesting improvement in survival with the use of patient navigators. Possibly the same could eventually be found with patient involvement in social media.
COMMENTARY
Social Media in Oncology: Does It Help Patients?
David Graham, MD
Disclosures | May 03, 2016
The growth of social media in medicine, particularly oncology, has been impressive. The uses to date have varied from live reporting of meeting presentations to community development and support in any number of diseases. The American Society of Clinical Oncology (ASCO) 2015 Annual Meeting had over 74,000 tweets in the month surrounding the actual meeting dates, leading to over 330 million impressions. An "impression" is a tweet that has been delivered to a feed. To relate it to the statistic above, tweets from the ASCO annual meeting were delivered to over 330 million feeds. The 2016 American College of Cardiology conference has had over 31,000 tweets leading to over 197 million impressions. This is just a small sampling of all the information that comes out of conferences.
Using social media for disease/treatment community development and support is also expanding. From dedicated Facebook pages to live Twitter chats, patients now interact with providers and advocates, often in real time. As I write this column, Symplur, a company that monitors and analyzes social media activity in medicine, reports 127 recurring Twitter chats in the upcoming week. Topics vary from rheumatoid arthritis, autism, and movement disorders to various malignancies, among many others.
Now that social media has a firm foothold in medicine, it becomes reasonable to ask whether it is having any impact on patient care or outcomes. This question has been raised in any number of supportive activities in medicine. There are certainly reports that online support groups benefit patients,[1] but the definition of benefit has tended to be somewhat nebulous at best. The first question to ask is, what is an appropriate thing to measure?
Now that social media has a firm foothold in medicine, it becomes reasonable to ask whether it is having any impact on patient care or outcomes.
In oncology, our usual measured outcome is survival, although quality of life is often co-reported. Quality of life, however, is rarely the primary outcome looked at in any intervention. There have been suggestions that support groups can improve survival in breast cancer, but at least one randomized trial failed to show any impact on survival in breast cancer patients.[2] Is survival the only outcome that we should measure? Can we accept improvements in quality of life as an actionable outcome? What if we show that patients who are involved in social media communities are more likely to be compliant with their care or be more open to clinical trial participation? Would that information be persuasive enough to have granting organizations, institutions, and payers be more open to providing support and recognition to the physicians and support staff involved in these activities?
Answering these questions will take a level of analysis and research that requires external support. To even get to the level of information and structure that granting organizations will be open to reviewing requires some firming up of ideas. There are physicians who are mulling these questions and starting down this path.[3] One such group in development is the Collaboration for Outcomes on Social Media in Oncology (COSMO). This group, of which I am a member, is looking at this with a blank slate, other than initially defining the best questions to ask. We have no hesitation—should the data point in this direction—saying that no positive impact can be determined by these efforts. We also have no problem saying that others may have thoughts on questions to be asked or approaches to take. In the spirit of crowdsourcing, we welcome any input. There are rumblings of an abstract to be presented at the next ASCO Annual Meeting suggesting improvement in survival with the use of patient navigators. Possibly the same could eventually be found with patient involvement in social media.
Challenging the Mantra of Randomized Controlled Trials to Answer Every Clinical Question
Medscape Oncology > Markman on Oncology
COMMENTARY
Challenging the Mantra of Randomized Controlled Trials to Answer Every Clinical Question
Maurie Markman, MD
Disclosures | May 02, 2016
Hello. I'm Dr Maurie Markman from Cancer Treatment Centers of America in Philadelphia.
I wanted to briefly comment on a very interesting paper that appeared in the Journal of Clinical Oncology and also to challenge, in a very direct way, one of the conclusions of the investigators. The paper is entitled "Role of Adjuvant Therapy in a Population-Based Cohort of Patients With Early-Stage Small-Cell Lung Cancer."[1]
Obviously, all oncologists are aware of the devastating impact of small cell lung cancer. The vast majority of patients, of course, present with advanced-stage disease. Chemotherapy certainly results in objective responses in a substantial number of patients, but the overall outcome today in small cell lung cancer is far from adequate.
In a setting where a patient is operated on who appears to have early-stage disease and the surgeons are able to leave the patient without evidence of disease that can be seen, the question that comes up is, is there a role for adjuvant therapy? It's an uncommon situation, so it is obviously difficult to do randomized controlled trials. This is also a provocative issue that has been on the minds of many oncologists for a long time.
The authors of this paper used data from the National Cancer Data Base and specifically looked at the issue of R0 resections. From 2003 to 2011, 1574 patients were identified and were classified as having received adjuvant therapy or not. The group of patients who received adjuvant chemotherapy had a median overall survival of 66 months versus 42 months for patients who had not received adjuvant chemotherapy, with a 5-year overall survival of 53% versus 40% (P < .01).
These are extremely important data and are quite relevant for physicians caring for individuals with small cell lung cancer in this clinical setting. What I want to comment on specifically was the final point of this otherwise excellent paper, whereby the authors concluded that these findings should be evaluated further in randomized controlled trials.
Do we really need a phase 3 randomized controlled trial to address this question? Is this necessary for every study where we see such overwhelming population-based data? It is hard to do these trials with this kind of an outcome. This is a chemotherapy-sensitive disease and these data show a positive outcome, so is it really necessary to conclude at the end of a paper that randomized controlled trials are necessary?
we need to begin to challenge this mantra of randomized controlled trials as the answer for every question.
Is such a conclusion put in a paper because the authors can only get it published in oncology journals if they put in this kind of statement? I think we need to begin to challenge this mantra of randomized controlled trials as the answer for every question. This is a very important issue, as the population-based data are impressive and are published in the peer-reviewed literature. I would submit that we should now consider this to be a standard-of-care option in the management of patients with early-stage small cell lung cancer.
Thank you for your attention.
miércoles, 4 de mayo de 2016
PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer
PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer
Hisham Mehanna, Ph.D., Wai-Lup Wong, F.R.C.R., Christopher C. McConkey, Ph.D., Joy K. Rahman, M.Sc., Max Robinson, Ph.D., Andrew G.J. Hartley, F.R.C.R., Christopher Nutting, Ph.D., Ned Powell, Ph.D., Hoda Al-Booz, F.R.C.R., Martin Robinson, F.R.C.R., Elizabeth Junor, F.R.C.R., Mohammed Rizwanullah, F.R.C.R., Sandra V. von Zeidler, Ph.D., Hulya Wieshmann, F.R.C.R., Claire Hulme, Ph.D., Alison F. Smith, M.Sc., Peter Hall, Ph.D., and Janet Dunn, Ph.D., for the PET-NECK Trial Management Group
N Engl J Med 2016; 374:1444-1454April 14, 2016DOI: 10.1056/NEJMoa1514493
Background
The role of image-guided surveillance as compared with planned neck dissection in the treatment of patients with squamous-cell carcinoma of the head and neck who have advanced nodal disease (stage N2 or N3) and who have received chemoradiotherapy for primary treatment is a matter of debate.
Methods
In this prospective, randomized, controlled trial, we assessed the noninferiority of positron-emission tomography–computed tomography (PET-CT)–guided surveillance (performed 12 weeks after the end of chemoradiotherapy, with neck dissection performed only if PET-CT showed an incomplete or equivocal response) to planned neck dissection in patients with stage N2 or N3 disease. The primary end point was overall survival.
Results
From 2007 through 2012, we recruited 564 patients (282 patients in the planned-surgery group and 282 patients in the surveillance group) from 37 centers in the United Kingdom. Among these patients, 17% had nodal stage N2a disease and 61% had stage N2b disease. A total of 84% of the patients had oropharyngeal cancer, and 75% had tumor specimens that stained positive for the p16 protein, an indicator that human papillomavirus had a role in the causation of the cancer. The median follow-up was 36 months. PET-CT–guided surveillance resulted in fewer neck dissections than did planned dissection surgery (54 vs. 221); rates of surgical complications were similar in the two groups (42% and 38%, respectively). The 2-year overall survival rate was 84.9% (95% confidence interval [CI], 80.7 to 89.1) in the surveillance group and 81.5% (95% CI, 76.9 to 86.3) in the planned-surgery group. The hazard ratio for death slightly favored PET-CT–guided surveillance and indicated noninferiority (upper boundary of the 95% CI for the hazard ratio, <1.50; P=0.004). There was no significant difference between the groups with respect to p16 expression. Quality of life was similar in the two groups. PET-CT–guided surveillance, as compared with neck dissection, resulted in savings of £1,492 (approximately $2,190 in U.S. dollars) per person over the duration of the trial. Conclusions
Survival was similar among patients who underwent PET-CT–guided surveillance and those who underwent planned neck dissection, but surveillance resulted in considerably fewer operations and it was more cost-effective. (Funded by the National Institute for Health Research Health Technology Assessment Programme and Cancer Research UK; PET-NECK Current Controlled Trials number, ISRCTN13735240.)
Presented in part at the Annual Meeting of the American Society of Clinical Oncology, Chicago, May 29–June 2, 2015.
Supported by academic grants from the National Institute for Health Research Health Technology Assessment Programme (06/302/129) and Cancer Research UK (C19677/A9674, for tissue-sample collection).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was published on March 23, 2016, at NEJM.org.
Address reprint requests to Dr. Mehanna at the Institute of Head and Neck Studies and Education, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom, or at h.mehanna@bham.ac.uk.
A complete list of investigators in the PET-NECK Trial Management Group is provided in the Supplementary Appendix, available at NEJM.org.
Hisham Mehanna, Ph.D., Wai-Lup Wong, F.R.C.R., Christopher C. McConkey, Ph.D., Joy K. Rahman, M.Sc., Max Robinson, Ph.D., Andrew G.J. Hartley, F.R.C.R., Christopher Nutting, Ph.D., Ned Powell, Ph.D., Hoda Al-Booz, F.R.C.R., Martin Robinson, F.R.C.R., Elizabeth Junor, F.R.C.R., Mohammed Rizwanullah, F.R.C.R., Sandra V. von Zeidler, Ph.D., Hulya Wieshmann, F.R.C.R., Claire Hulme, Ph.D., Alison F. Smith, M.Sc., Peter Hall, Ph.D., and Janet Dunn, Ph.D., for the PET-NECK Trial Management Group
N Engl J Med 2016; 374:1444-1454April 14, 2016DOI: 10.1056/NEJMoa1514493
Background
The role of image-guided surveillance as compared with planned neck dissection in the treatment of patients with squamous-cell carcinoma of the head and neck who have advanced nodal disease (stage N2 or N3) and who have received chemoradiotherapy for primary treatment is a matter of debate.
Methods
In this prospective, randomized, controlled trial, we assessed the noninferiority of positron-emission tomography–computed tomography (PET-CT)–guided surveillance (performed 12 weeks after the end of chemoradiotherapy, with neck dissection performed only if PET-CT showed an incomplete or equivocal response) to planned neck dissection in patients with stage N2 or N3 disease. The primary end point was overall survival.
Results
From 2007 through 2012, we recruited 564 patients (282 patients in the planned-surgery group and 282 patients in the surveillance group) from 37 centers in the United Kingdom. Among these patients, 17% had nodal stage N2a disease and 61% had stage N2b disease. A total of 84% of the patients had oropharyngeal cancer, and 75% had tumor specimens that stained positive for the p16 protein, an indicator that human papillomavirus had a role in the causation of the cancer. The median follow-up was 36 months. PET-CT–guided surveillance resulted in fewer neck dissections than did planned dissection surgery (54 vs. 221); rates of surgical complications were similar in the two groups (42% and 38%, respectively). The 2-year overall survival rate was 84.9% (95% confidence interval [CI], 80.7 to 89.1) in the surveillance group and 81.5% (95% CI, 76.9 to 86.3) in the planned-surgery group. The hazard ratio for death slightly favored PET-CT–guided surveillance and indicated noninferiority (upper boundary of the 95% CI for the hazard ratio, <1.50; P=0.004). There was no significant difference between the groups with respect to p16 expression. Quality of life was similar in the two groups. PET-CT–guided surveillance, as compared with neck dissection, resulted in savings of £1,492 (approximately $2,190 in U.S. dollars) per person over the duration of the trial. Conclusions
Survival was similar among patients who underwent PET-CT–guided surveillance and those who underwent planned neck dissection, but surveillance resulted in considerably fewer operations and it was more cost-effective. (Funded by the National Institute for Health Research Health Technology Assessment Programme and Cancer Research UK; PET-NECK Current Controlled Trials number, ISRCTN13735240.)
Presented in part at the Annual Meeting of the American Society of Clinical Oncology, Chicago, May 29–June 2, 2015.
Supported by academic grants from the National Institute for Health Research Health Technology Assessment Programme (06/302/129) and Cancer Research UK (C19677/A9674, for tissue-sample collection).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was published on March 23, 2016, at NEJM.org.
Address reprint requests to Dr. Mehanna at the Institute of Head and Neck Studies and Education, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom, or at h.mehanna@bham.ac.uk.
A complete list of investigators in the PET-NECK Trial Management Group is provided in the Supplementary Appendix, available at NEJM.org.
Medical Error Is Third Leading Cause of Death in US
Medscape Medical News
Medical Error Is Third Leading Cause of Death in US
Marcia Frellick
May 03, 2016
Medical error is the third leading cause of death in the United States, after heart disease and cancer, according to findings published today in BMJ.
As such, medical errors should be a top priority for research and resources, say authors Martin Makary, MD, MPH, professor of surgery, and research fellow Michael Daniel, from Johns Hopkins University School of Medicine in Baltimore, Maryland.
But accurate, transparent information about errors is not captured on death certificates, which are the documents the Centers for Disease Control and Prevention (CDC) uses for ranking causes of death and setting health priorities. Death certificates depend on International Classification of Diseases (ICD) codes for cause of death, so causes such as human and system errors are not recorded on them.
And it's not just the US. According to the World Health Organization, 117 countries code their mortality statistics using the ICD system as the primary health status indicator.
The authors call for better reporting to help capture the scale of the problem and create strategies for reducing it.
Cancer and Heart Disease Get the Attention
"Top-ranked causes of death as reported by the CDC inform our country's research funding and public health priorities," Dr Makary said in an university press release. "Right now, cancer and heart disease get a ton of attention, but since medical errors don't appear on the list, the problem doesn't get the funding and attention it deserves."
He adds: "Incidence rates for deaths directly attributable to medical care gone awry haven't been recognized in any standardized method for collecting national statistics. The medical coding system was designed to maximize billing for physician services, not to collect national health statistics, as it is currently being used."
The researchers examined four studies that analyzed medical death rate data from 2000 to 2008. Then, using hospital admission rates from 2013, they extrapolated that, based on 35,416,020 hospitalizations, 251,454 deaths stemmed from a medical error.
That number of deaths translates to 9.5% of all deaths each year in the US — and puts medical error above the previous third-leading cause, respiratory disease.
In 2013, 611,105 people died of heart disease, 584,881 died of cancer, and 149,205 died of chronic respiratory disease, according to the CDC.
The new estimates are considerably higher than those in the 1999 Institute of Medicine report "To Err Is Human." However, the authors note that the data used for that report "is limited and outdated."
Strategies for Change
The authors suggest several changes, including making errors more visible so their effects can be understood. Often, discussions about prevention occur in limited and confidential forums, such as a department's morbidity and mortality conference.
Another is changing death certificates to include not just the cause of death, but an extra field asking whether a preventable complication stemming from the patient's care contributed to the death.
The authors also suggest that hospitals carry out a rapid and efficient independent investigation into deaths to determine whether error played a role. A root cause analysis approach would help while offering the protection of anonymity, they say.
Standardized data collection and reporting are also needed to build an accurate national picture of the problem.
Jim Rickert, MD, an orthopedist in Bedford, Indiana, and president of the Society for Patient Centered Orthopedics, told Medscape Medical News he was not surprised the errors came in at number 3 and that even those calculations don't tell the whole story.
"That doesn't even include doctors' offices and ambulatory care centers," he notes. "That's only inpatient hospitalization resulting in errors."
"I think most people underestimate the risk of error when they seek medical care," he said.
He agrees that adding a field to death certificates to indicate medical error is likely the way to get medical errors the attention they deserve.
"It's public pressure that brings about change. Hospitals have no incentive to publicize errors; neither do doctors or any other provider," he said.
However, such a major step as adding error information to death certificates is unlikely if not accompanied by tort reform, he said.
Still, this study helps emphasize the prevalence of errors, he said.
Human error is inevitable, the authors acknowledge, but "we can better measure the problem to design safer systems mitigating its frequency, visibility, and consequences."
They add that most errors aren't caused by bad doctors but by systemic failures and should 'not be addressed with punishment or legal action.
The authors and Dr Rickert disclosed no relevant financial relationships.
BMJ. Published online May 3, 2016. Full text
martes, 3 de mayo de 2016
CCR2 Inhibitor Plus FOLFIRINOX Shows Promise For Early-Stage Pancreatic Cancer
CCR2 Inhibitor Plus FOLFIRINOX Shows Promise For Early-Stage Pancreatic Cancer
Preliminary research points to a potential role for CCR2 inhibition in the treatment of borderline resectable and locally advanced ductal adenocarcinoma of the pancreas
Date: 05 Apr 2016
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Drug Development / Pancreatic Cancer
medwireNews: A novel agent targeting the CCL2–CCR2 chemokine axis may have promise as an neoadjuvant treatment alongside chemotherapy in patients with borderline resectable and locally advanced pancreatic cancer, suggest early trial findings indicating the inhibitor to be well tolerated.
“No neoadjuvant therapy currently provides a durable clinical effect in patients with pancreatic ductal adenocarcinoma”, observe David Linehan, from the University of Rochester Medical Center in New York, USA, and co-workers.
“CCR2 inhibition is a promising therapeutic strategy and should be explored in further clinical trials.”
The open-label phase 1b trial included a total of eight treatment-naïve patients given six cycles of FOLFIRINOX and 39 patients who received chemotherapy alongside PF-04136309, an oral small molecule CCR2 inhibitor.
Just one of the patients given PF-04136309 at the starting dose of 500 mg twice daily required dose reduction; the 500 mg twice daily dose was thus fixed as the recommended dosing for phase II studies, say the researchers.
Six of the eight FOLFIRINOX-only patients and 39 of the combined treatment patients were followed-up for toxicity for a median of 72 and 77 days, respectively.
Two patients given PF-04136309 terminated treatment early due to treatment-related toxicity, with grade 3 or more serious events occurring in at least 10% of the group including neutropenia, febrile neutropenia, lymphopenia, diarrhoea and hypokalaemia.
Similarly, grade 3 or above neutropenia, febrile neutropenia, anaemia, lymphopenia, diarrhoea, hypoalbuminaemia and hypokalaemia were reported in at least 10% of patients given FOLFIRINOX only, one of whom ended treatment early.
“In summary, PF-04136309 in combination with FOLFIRINOX did not result in additional toxicity at the recommended phase 2 dose”, the team writes in The Lancet Oncology.
Moreover, repeated imaging in 33 of the patients given chemotherapy plus PF-04136309showed that 48.5% had a partial response, a significantly higher rate than the prespecified expectation of 25.0% for FOLFIRINOX alone, the authors observe.
And 97% of the 33 patients achieved at least local tumour control, with just one patient experiencing disease progression and no reports of distant metastases.
By contrast, none of the five FOLFIRINOX-only patients assessed for efficacy achieved an objective treatment response; four had stable disease and one patient had distant metastases.
David Linehan et al report that lesion size reduced sufficiently to allow surgery in 39% of the 33 patients given the combined treatment. Seven of 10 patients who underwent resection achieved an R0 outcome and five had negative lymph nodes; six patients underwent additional neoadjuvant radiotherapy and chemotherapy.
Of note, patients who received FOLFIRINOX alone experienced an average 68.20% decrease in CCR2-positive monocytes in their bone marrow after treatment and a mean 42.67% increase in CCR2-positive monocytes in their blood samples.
By contrast, after PF-04136309 plus FOLFIRINOX treatment, patients had a 66.43% increase in bone marrow CCR2-positive monocytes and a 36.56% decrease in circulating CCR2-positive monocytes.
“FOLFIRINOX plus PF-04136309 prevented CCR2-positive monocyte egress from the bone marrow to the peripheral blood and reduced tumour-associated macrophage infiltrate at the primary tumour”, the researchers propose.
“The subsequent reversal of immune suppression within the tumour microenvironment, and the influx of tumour-infiltrating lymphocytes, suggests a restoration of anti-tumour immunity.”
Noting that this effect was strongest in patients who achieved a RECIST objective response, the authors suggest that “[a]lthough interpretation of this finding is limited by the small study population, this Biomarker evidence suggests that the clinical activity seen with FOLFIRINOX plus PF-04136309 correlated with target engagement.”
They conclude: “Our results support a potential therapeutic effect of use of targeted therapy to disrupt the CCL2–CCR2 chemokine axis in pancreatic ductal adenocarcinoma.”
Reference
Nywening TM, Wang-Gillam A, Sanford DE, et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol 2016; Advance online publication 4 April. http://dx.doi.org/10.1016/S1470-2045(16)00078-4
Preliminary research points to a potential role for CCR2 inhibition in the treatment of borderline resectable and locally advanced ductal adenocarcinoma of the pancreas
Date: 05 Apr 2016
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Drug Development / Pancreatic Cancer
medwireNews: A novel agent targeting the CCL2–CCR2 chemokine axis may have promise as an neoadjuvant treatment alongside chemotherapy in patients with borderline resectable and locally advanced pancreatic cancer, suggest early trial findings indicating the inhibitor to be well tolerated.
“No neoadjuvant therapy currently provides a durable clinical effect in patients with pancreatic ductal adenocarcinoma”, observe David Linehan, from the University of Rochester Medical Center in New York, USA, and co-workers.
“CCR2 inhibition is a promising therapeutic strategy and should be explored in further clinical trials.”
The open-label phase 1b trial included a total of eight treatment-naïve patients given six cycles of FOLFIRINOX and 39 patients who received chemotherapy alongside PF-04136309, an oral small molecule CCR2 inhibitor.
Just one of the patients given PF-04136309 at the starting dose of 500 mg twice daily required dose reduction; the 500 mg twice daily dose was thus fixed as the recommended dosing for phase II studies, say the researchers.
Six of the eight FOLFIRINOX-only patients and 39 of the combined treatment patients were followed-up for toxicity for a median of 72 and 77 days, respectively.
Two patients given PF-04136309 terminated treatment early due to treatment-related toxicity, with grade 3 or more serious events occurring in at least 10% of the group including neutropenia, febrile neutropenia, lymphopenia, diarrhoea and hypokalaemia.
Similarly, grade 3 or above neutropenia, febrile neutropenia, anaemia, lymphopenia, diarrhoea, hypoalbuminaemia and hypokalaemia were reported in at least 10% of patients given FOLFIRINOX only, one of whom ended treatment early.
“In summary, PF-04136309 in combination with FOLFIRINOX did not result in additional toxicity at the recommended phase 2 dose”, the team writes in The Lancet Oncology.
Moreover, repeated imaging in 33 of the patients given chemotherapy plus PF-04136309showed that 48.5% had a partial response, a significantly higher rate than the prespecified expectation of 25.0% for FOLFIRINOX alone, the authors observe.
And 97% of the 33 patients achieved at least local tumour control, with just one patient experiencing disease progression and no reports of distant metastases.
By contrast, none of the five FOLFIRINOX-only patients assessed for efficacy achieved an objective treatment response; four had stable disease and one patient had distant metastases.
David Linehan et al report that lesion size reduced sufficiently to allow surgery in 39% of the 33 patients given the combined treatment. Seven of 10 patients who underwent resection achieved an R0 outcome and five had negative lymph nodes; six patients underwent additional neoadjuvant radiotherapy and chemotherapy.
Of note, patients who received FOLFIRINOX alone experienced an average 68.20% decrease in CCR2-positive monocytes in their bone marrow after treatment and a mean 42.67% increase in CCR2-positive monocytes in their blood samples.
By contrast, after PF-04136309 plus FOLFIRINOX treatment, patients had a 66.43% increase in bone marrow CCR2-positive monocytes and a 36.56% decrease in circulating CCR2-positive monocytes.
“FOLFIRINOX plus PF-04136309 prevented CCR2-positive monocyte egress from the bone marrow to the peripheral blood and reduced tumour-associated macrophage infiltrate at the primary tumour”, the researchers propose.
“The subsequent reversal of immune suppression within the tumour microenvironment, and the influx of tumour-infiltrating lymphocytes, suggests a restoration of anti-tumour immunity.”
Noting that this effect was strongest in patients who achieved a RECIST objective response, the authors suggest that “[a]lthough interpretation of this finding is limited by the small study population, this Biomarker evidence suggests that the clinical activity seen with FOLFIRINOX plus PF-04136309 correlated with target engagement.”
They conclude: “Our results support a potential therapeutic effect of use of targeted therapy to disrupt the CCL2–CCR2 chemokine axis in pancreatic ductal adenocarcinoma.”
Reference
Nywening TM, Wang-Gillam A, Sanford DE, et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol 2016; Advance online publication 4 April. http://dx.doi.org/10.1016/S1470-2045(16)00078-4
Trastuzumab Plus Lapatinib Show Promise For HER2-Positive Colorectal Cancer
Trastuzumab Plus Lapatinib Show Promise For HER2-Positive Colorectal Cancer
Patients with heavily pretreated, metastatic HER2-positive colorectal cancer may respond to trastuzumab plus lapatinib
Date: 22 Apr 2016
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Colon Cancer / Rectal Cancer / Translational Research
medwireNews: The combination of trastuzumab and lapatinib is both active and well tolerated in patients with HER2-positive, metastatic, treatment-refractory colorectal cancer, suggest findings from the proof-of-concept HERACLES trial.
“The results of this study could change the day-to-day clinical care management of patients with advanced HER2-positive colorectal cancer”, say Silvia Marsoni, from Istituto di Candiolo in Italy, and co-authors in The Lancet Oncology.
“Our findings could lead to the use of trastuzumab and lapatinib in earlier lines of treatment, with a possibility of chemotherapy-free regimens, for patients with HER2-positive tumours”, they believe.
The phase II trial included 27 patients whose tumours were HER2-positive and wild-type for KRAS exon 2, and had at least one measurable lesion. The participants had progressed during or within 6 months of receiving a standard of care treatment, including regimens with the Epidermal growth factor receptor (EGFR) inhibitors, cetuximab or panitumumab.
After a median of 94 weeks, eight (30%) patients had achieved an objective response by RECIST v1.1 criteria, including one complete response and seven partial responses. Twelve patients had stable disease, eight of whom did not experience progression for at least 16 weeks.
Two patients experienced disease progression before the 8-week radiological assessment but 84% of the 25 patients assessed at this point showed tumour shrinkage, the investigators observe.
In all, 59% of the group achieved disease control for at least 16 weeks and the median progression-free survival (PFS) was 21 weeks. Median overall survival was 46 weeks, with 45% of the 27 patients alive at 1 year.
Diarrhoea, rash, fatigue, Paronychia and conjunctivitis were the most common side effects, reported in 78%, 48%, 48%, 33% and 19% of the patients, respectively. Six (22%) of the patients experienced grade 3 side effects, namely fatigue (n=4), skin rash (n=1) and elevated bilirubin (n=1), but there were no grade 4 or 5 events or drug-related serious events.
Of note, all but one of the patients who achieved an objective response had a HER2 score of 3+ on Immunohistochemistry whereas just 10 of the 17 patients with stable disease or progression had a 3+ score.
And further analysis showed that objective response was significantly more likely in patients with a HER2 Gene copy number above 9.45 than those with a lower number, at 44% versus 0%. Median PFS was also higher, at 29 versus 16 weeks.
“Our results show that HER2 Amplification is a clinically relevant genetic alteration in metastatic colorectal cancer”, conclude Silvia Marsoni et al.
“This alteration can be screened for with established diagnostic tools, can be acted on at the therapeutic level, and occurs in 3–5% of patients with KRAS Codon 12/13 wild-type metastatic colorectal cancer, similar to that of other genetic alterations for which licensed drugs are effective (eg, in lung cancer).”
Describing the results as “extraordinary” for a group of heavily pretreated patients, the author of an accompanying comment said that, combined with findings from the MyPathway basket trial of colorectal cancer patients with a druggable target, the data “define a new standard of routine therapy” for HER2-positive patients.
Hans-Joachim Schmoll, from Martin-Luther-Universität Halle-Wittenberg in Germany, now questions the optimal treatment combination and timing of treatments targeting HER2 and EGFR in colorectal cancer patients and where best to focus future research.
“While this anti-HER2 strategy could be adopted for routine salvage therapy and is being investigated in earlier lines, ongoing research is also investigating targeting of HER3 and the combined inhibition of EGFR and HER2–4”, he writes, noting that HER3 is expressed in up to three-quarters of colorectal tumours.
References
Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol 2016; 20 April. DOI: http://dx.doi.org/10.1016/S1470-2045(16)00150-9
Schmoll H-J. Targeting HER2: precision oncology for colorectal cancer. Lancet Oncol 2016; 20 April. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30039-0
Patients with heavily pretreated, metastatic HER2-positive colorectal cancer may respond to trastuzumab plus lapatinib
Date: 22 Apr 2016
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Colon Cancer / Rectal Cancer / Translational Research
medwireNews: The combination of trastuzumab and lapatinib is both active and well tolerated in patients with HER2-positive, metastatic, treatment-refractory colorectal cancer, suggest findings from the proof-of-concept HERACLES trial.
“The results of this study could change the day-to-day clinical care management of patients with advanced HER2-positive colorectal cancer”, say Silvia Marsoni, from Istituto di Candiolo in Italy, and co-authors in The Lancet Oncology.
“Our findings could lead to the use of trastuzumab and lapatinib in earlier lines of treatment, with a possibility of chemotherapy-free regimens, for patients with HER2-positive tumours”, they believe.
The phase II trial included 27 patients whose tumours were HER2-positive and wild-type for KRAS exon 2, and had at least one measurable lesion. The participants had progressed during or within 6 months of receiving a standard of care treatment, including regimens with the Epidermal growth factor receptor (EGFR) inhibitors, cetuximab or panitumumab.
After a median of 94 weeks, eight (30%) patients had achieved an objective response by RECIST v1.1 criteria, including one complete response and seven partial responses. Twelve patients had stable disease, eight of whom did not experience progression for at least 16 weeks.
Two patients experienced disease progression before the 8-week radiological assessment but 84% of the 25 patients assessed at this point showed tumour shrinkage, the investigators observe.
In all, 59% of the group achieved disease control for at least 16 weeks and the median progression-free survival (PFS) was 21 weeks. Median overall survival was 46 weeks, with 45% of the 27 patients alive at 1 year.
Diarrhoea, rash, fatigue, Paronychia and conjunctivitis were the most common side effects, reported in 78%, 48%, 48%, 33% and 19% of the patients, respectively. Six (22%) of the patients experienced grade 3 side effects, namely fatigue (n=4), skin rash (n=1) and elevated bilirubin (n=1), but there were no grade 4 or 5 events or drug-related serious events.
Of note, all but one of the patients who achieved an objective response had a HER2 score of 3+ on Immunohistochemistry whereas just 10 of the 17 patients with stable disease or progression had a 3+ score.
And further analysis showed that objective response was significantly more likely in patients with a HER2 Gene copy number above 9.45 than those with a lower number, at 44% versus 0%. Median PFS was also higher, at 29 versus 16 weeks.
“Our results show that HER2 Amplification is a clinically relevant genetic alteration in metastatic colorectal cancer”, conclude Silvia Marsoni et al.
“This alteration can be screened for with established diagnostic tools, can be acted on at the therapeutic level, and occurs in 3–5% of patients with KRAS Codon 12/13 wild-type metastatic colorectal cancer, similar to that of other genetic alterations for which licensed drugs are effective (eg, in lung cancer).”
Describing the results as “extraordinary” for a group of heavily pretreated patients, the author of an accompanying comment said that, combined with findings from the MyPathway basket trial of colorectal cancer patients with a druggable target, the data “define a new standard of routine therapy” for HER2-positive patients.
Hans-Joachim Schmoll, from Martin-Luther-Universität Halle-Wittenberg in Germany, now questions the optimal treatment combination and timing of treatments targeting HER2 and EGFR in colorectal cancer patients and where best to focus future research.
“While this anti-HER2 strategy could be adopted for routine salvage therapy and is being investigated in earlier lines, ongoing research is also investigating targeting of HER3 and the combined inhibition of EGFR and HER2–4”, he writes, noting that HER3 is expressed in up to three-quarters of colorectal tumours.
References
Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol 2016; 20 April. DOI: http://dx.doi.org/10.1016/S1470-2045(16)00150-9
Schmoll H-J. Targeting HER2: precision oncology for colorectal cancer. Lancet Oncol 2016; 20 April. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30039-0
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